This invention relates to a process for the preparation of deacetoxycephalosporins. In particular, it relates to an improved process for the conversion of penicillin sulfoxide esters to deacetoxycephalosporin esters.
In U.S. Pat. No. 3,275,626 Morin and Jackson describe the penicillin sulfoxide rearrangement reaction wherein the thiazolidine ring of a penicillin sulfoxide is expanded to the dihydrothiazine ring of the desacetoxycephalosporin. This process provided the first practical method for the preparation of the deacetoxycephalosporins, the 3-methyl-3-cephem compounds, and also povided for the first time a method for the preparation of cephalosporin compounds which did not depend upon cephalosporin C as a starting material.
In U.S. Pat. No. 3,647,787 Cooper describes an improved process for the conversion of penicillin sulfoxides to deacetoxycephalosporins which comprises heating the penicillin sulfoxide ester under acid conditions in a tertiary carboxamide, a urea derivative, and/or a sulfonamide. A further improved process is taught in U.S. Pat. No. 3,591,585 issued July 6, 1971. Therein the use of a sulfonic acid catalyst in a tertiary carboxamide solvent is described. More recently, U.S. Pat. No. 3,725,397 and U.S. Pat. No. 3,725,399 describe certain acid catalysts which can be employed in the ring expansion process. In the former patent, nitrogen base complexes formed with lower alkyl, phenyl lower alkyl, or phenyl dihydrogen phosphates are taught as useful acid catalysts in the rearrangement. The latter patent describes the use of certain amine salts of sulfonic acids, phosphorus acid, or trifluoroacetic acid in the ring expansion process.
The conversion of penicillin sulfoxide esters into deacetoxycephalosporins is the commercial method of choice for the preparation of the desacetoxycephalosporins. For example, the widely prescribed antibiotic, cephalexin, can be prepared from an intermediate 7-acylamidodeacetoxycephalosporanic acid ester prepared via the ring expansion of a penicillin sulfoxide ester. For example, a 6-acylamidopenicillanic acid ester sulfoxide such as an ester of 6-phenoxyacetamidopenicillanic acid sulfoxide is reacted under the ring expansion conditions to yield the corresponding ester of the 7-phenoxyacetamido-deacetoxycephalosporanic acid (an ester of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid). The 7-phenoxyacetyl side chain of the ring expanded cephalosporin product is then removed by employing the well known side chain cleavage reaction conditions to provide the cephalosporin nucleus ester, an ester of 7-amino-3-methyl-3-cephem-4-carboxylic acid. For example, the intermediate ring expanded ester can be reacted in an inert solvent with phosphorus pentachloride to form the imino chloride, which on reaction with a lower alkanol forms the unstable imino ether. The imino ether decomposes to effect N-deacylation of 7-phenoxyacetyl side chain with formation of the 7-amino nucleus ester. The nucleus ester is then acylated with a suitably protected phenylglycine derivative to provide the ester of 7-phenylglycylamido-3-methyl-3-cephem-4-carboxylic acid ester having the amino group in the 7-position side chain protected. The amino protecting group and the ester group of the C.sub.4 carboxyl group are removed to provide the antibiotic cephalexin.
In view of the commercial importance of the antibiotic cephalexin, there exists a need for enhanced yields in the production thereof. One of the main steps in the overall process for the preparation of this antibiotic is the penicillin sulfoxide ring expansion reaction. Accordingly, improved yields of the intermediate deacetoxycephalosporin prepared by the ring expansion process would lead to enhanced yields in the production of the antibiotic.